5-116446797-T-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_020796.5(SEMA6A):c.2909A>C(p.Gln970Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00573 in 1,613,124 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0059 (31 hom.)
• Consequence: SEMA6A NM_020796.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.73

Genes affected

SEMA6A (HGNC:10738): (semaphorin 6A) Predicted to enable identical protein binding activity; signaling receptor binding activity; and transmembrane signaling receptor activity. Involved in cellular response to vascular endothelial growth factor stimulus; negative regulation of cell adhesion involved in sprouting angiogenesis; and negative regulation of signal transduction. Predicted to be integral component of membrane. Predicted to be active in extracellular space. Predicted to be integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007560551).
• BP6: Variant 5-116446797-T-G is Benign according to our data. Variant chr5-116446797-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 718147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 31 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEMA6A	NM_020796.5	c.2909A>C	p.Gln970Pro	missense_variant	19/19	ENST00000343348.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEMA6A	ENST00000343348.11	c.2909A>C	p.Gln970Pro	missense_variant	19/19	1	NM_020796.5	P4

Frequencies

GnomAD3 genomes AF: 0.00421 AC: 640 AN: 152168 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00125

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00584

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00691

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00470 AC: 1159 AN: 246662 Hom.: 5 AF XY: 0.00464 AC XY: 622 AN XY: 133916

Gnomad AFR exome AF: 0.00119

Gnomad AMR exome AF: 0.00146

Gnomad ASJ exome AF: 0.00722

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000986

Gnomad FIN exome AF: 0.00771

Gnomad NFE exome AF: 0.00720

Gnomad OTH exome AF: 0.00334

GnomAD4 exome AF: 0.00589 AC: 8600 AN: 1460838 Hom.: 31 Cov.: 31 AF XY: 0.00582 AC XY: 4231 AN XY: 726622

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.00159

Gnomad4 ASJ exome AF: 0.00801

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000975

Gnomad4 FIN exome AF: 0.00786

Gnomad4 NFE exome AF: 0.00671

Gnomad4 OTH exome AF: 0.00545

GnomAD4 genome AF: 0.00420 AC: 640 AN: 152286 Hom.: 1 Cov.: 32 AF XY: 0.00396 AC XY: 295 AN XY: 74460

Gnomad4 AFR AF: 0.00125

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00720

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00584

Gnomad4 NFE AF: 0.00691

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00659 Hom.: 7

Bravo AF: 0.00379

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00908 AC: 35

ESP6500AA AF: 0.00120 AC: 5

ESP6500EA AF: 0.00733 AC: 62

ExAC AF: 0.00445 AC: 539

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	SEMA6A: BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	May 08, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	23
DANN	Uncertain	0.99
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.0076	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.2	N;N;N;N;N
REVEL	Benign	0.23
Sift	Uncertain	0.012	D;D;D;D;D
Sift4G	Benign	0.15	T;T;D;D;T
Polyphen		0.96, 0.94	.;.;D;P;.
Vest4		0.59
MVP		0.41
MPC		0.71
ClinPred		0.026	T
GERP RS		4.3
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs200578077; hg19: chr5-115782493; COSMIC: COSV99030636; COSMIC: COSV99030636;